It is imperative that an in vitro model of Alzheimer's Disease be developed; this would greatly improve studies of the mechanism(s) of Alzheimer's disease and allow screening of potential therapeutic agents. In addition, if the model were genetically manipulable, then the gene or genes important for the development of the Alzheimer's pathology could be determined. No such model has been available previously, but data presented in this proposal suggest that an in vitro model of Alzheimer's disease has now been developed (see Preliminary Results). This consists of long-term reaggregating brain cultures of trisomy 16 mouse central nervous system. It is proposed that these studies be extended by (1) characterizing the reaggregating brain cultures of Ts16 mice and control littermates for beta- amyloid production, abnormally phosphorylated tau (i.e., the mouse equivalent of the Alz-50 target), phosphorylated neurofilament, neuronal density vs. time, paired helical filaments, and APP751/APP695 mRNA ratios; and (2) producing temperature-sensitive immortalized T16 neural and glial cells, then transfecting the cell with a reporter expression construct and including the cells in the reaggregating cultures. The long-term goal of this project is to develop and characterize an in vitro model of Alzheimer's disease that will be genetically manipulable. This should allow an evaluation of the region of mouse chromosome 16 that is important for the development of the changes associated with Alzheimer's disease, and, ultimately, determination of the important gene or genes.